Discovery of PF-5190457, a Potent, Selective, and Orally Bioavailable Ghrelin Receptor Inverse Agonist Clinical Candidate
Discovery of PF-5190457, a Potent, Selective, and Orally Bioavailable Ghrelin Receptor Inverse Agonist Clinical Candidate
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DOI：
10.1021/ml400473x
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发表时间：
2014-05-01
影响因子：
4.2
通讯作者：
Zhang, Yingxin
中科院分区：
文献类型：
--
作者：
Bhattacharya, Samit K.;Andrews, Kim;Zhang, Yingxin
描述了从螺-氮杂环丁烷-哌啶系列中鉴定有效的、高选择性的口服生物可利用的胃饥饿素受体反向激动剂。这一系列的例子有前途的体内药代动力学和增加葡萄糖刺激的胰岛素分泌在人类整个和分散的胰岛。一种基于物理化学的策略，以增加生长素释放肽受体效力的亲脂效率，并保持低清除率和令人满意的渗透性，同时减少脱靶药理学，导致16 h的发现。化合物16 h具有胃饥饿素受体药理学和脱靶选择性的上级平衡。基于其有前途的药理学和安全性特征，16 h被推进到人体临床试验。
The identification of potent, highly selective orally bioavailable ghrelin receptor inverse agonists from a spiro-azetidino-piperidine series is described. Examples from this series have promising in vivo pharmacokinetics and increase glucose-stimulated insulin secretion in human whole and dispersed islets. A physicochemistry-based strategy to increase lipophilic efficiency for ghrelin receptor potency and retain low clearance and satisfactory permeability while reducing off-target pharmacology led to the discovery of 16h. Compound 16h has a superior balance of ghrelin receptor pharmacology and off-target selectivity. On the basis of its promising pharmacological and safety profile, 16h was advanced to human clinical trials.